Pathology

Front 1

What are the eary stages of hypoxic cell injury?

Back 1

1) Decreased ATP synthesis
--failure of Na/K ATPase pump so get influx of Na and H20 from EC space

--hydropic change/cell swelling
--ER & mitochondrial swelling

2) disaggregation of ribosomes and failed protein synthesis

Front 2

Late stage of hypoxic cell injury

Back 2

1) membrane damage to plasma and to lysosomal organelle membranes
REVERSIBLE:
--MYELIN FIGURES=cytoplasmic bodies in damaged cells made of whorls of membranes from damaged cytoplasmic organelles...taken up into autophagosomes

--cell blebs

2) Cell death: SIGNS
--irreversible damage to cell membranes
--Nuclear changes: Pyknosis, karyolysis, karyorrhexis

--enzymes like LDH (from ruptured RBCs) CPK (from cardiac or skeletal muscle), AST/ALT (from liver)

Front 3

Coagulative necrosis

Back 3

1)results from interruption of blood supply, denaturation of proteins

2) seen in organs supplied by end arteries with little collateral such as heart and kidney

3) General architecture same

Front 4

Liquefactive necrosis

Back 4

1) enzymatic liquification of necrotic tissue

2) usually in CNS

3) From interupted blood supply OR in area of bacterial infection

Front 5

What is caseous necrosis?

Back 5

seen most commonly in tuberculous & fungal granulomas

Architecture not preserved
Looks "cheese-like"
increased affinity for acidophilic dyes

Front 6

fibrinoid necrosis

Back 6

fibrin-like proteinatcious material deposited in walls of small BV's

often as part of immune-mediated vasculitis (or from AI dz like SLE)

looks smudgy pink in vascular walls

Front 7

fat necrosis

Back 7

Lipase and other lytic enzymes released from damaged pancreatic cells, and permeate fat cells

Usually occurs with acute pancreatitis

See acute imflammation, hemorrhage, calcium soap formation, clustering of lipen-laden macrophages

Front 8

What is steatosis

Back 8

accumulation of intracellular parencymal triglycerides

--most frequently in liver, heart and kidney

--have overproduction of fat, decreased use in cells, and dec mobilization from cells

Front 9

metastatic calcification vs. dystrophic

Back 9

metastatic= caused by hypercalcemia (most often from inc PTH)

dystrophic=occurs in previously damaged tissues
NOT caused by hypercalcemia

Front 10

Inflammatory processes

Back 10

1) exudation of fluid from vessels

2)attraction of leukocytes to injury so they can engulf and destroy

3) activation of chemical mediators

4) proteolytic degredation of extracellular debris

5) restoration of injured tissue to normal function

Front 11

inflammatory adhesion molecules
SELECTINS

Back 11

1) induced by IL-1 and TNF
L-selectins on neutrophils bind endothelial mucin-like molecules

E and P selectins on endothelial cells bind to surface of leukocytes

P-selectins in weibel-Palade bodies and platelet alpha granules --> go to plasma membrane after stimulated by histamine or thrombin

Front 12

inflammatory adhesion molecules:ICAMS

Back 12

ICAM-1 and ICAM-2=
expressed on endothelial cells and bind to integrin molecules on leukocytes

VCAMS=
expressed on endothelial cells and bind to integrin molecules on leukocytes

Front 13

vasoactive changes in acute inflammation

Back 13

First have brief vasoconstriction, then dilation (get increased blood flow to affected)

Front 14

increased capillary permeability in acute inflammation

Back 14

causes leakage of proteinaceous fluid which causes edema

caused by endothelial changes

Front 15

Neutrophils

Back 15

arrive during first 24 hours
CAUSES:
--bacterial infections
--infarction or other causes of acute inflammation

**Note that early release of neutrophils is from the bone marrow reserve

Front 16

monocytes/macrophages

Back 16

replace neutrophils after 2-3 days

can engulf large particles and can divide & proliferate within inflamed tissue

Front 17

lymphocytes

Back 17

viral infections (influenza, rubella, mono)
also see in TB

Front 18

eosinophils

Back 18

allergic reations
parasitic infections

also, hodgkins and polyarteritis nodosa)

Front 19

mast cells and basophils

Back 19

sources of histamine

see with CML and other myeloproliferative dzs

Front 20

How do cells respond to leukocytes?

Back 20

1) emigration
--MARGINATION
(leukocytes to outer margin of blood flow adjacent to endothelium)

--PAVEMENTING:
(leukocytes line endothelial surface)

--ROLLING
(endothelial selecins loosely bind leukocytes and help roll along endothelial surface

--ADHESION
mediated by ICAMs and integrins

--TRANSMIGRATION
leukocytes move across endothelium
mediated by PECAM-1 on leukocytes and endothelium

Front 21

chemotaxis

Back 21

process by which leukocytes move towards injury

chemotactic factors for neutrophils include:
1) products from bacteria
2)compllement components (C5a)
3)arachidonic acid metabolites (LTB4, HETE, and kallikrein)

Front 22

opsonization

Back 22

facilitates phagocytosis by coating with opsonins which help immobolize particles on surface of phagocyte

Types of opsonins:
1)IgG
2) C3b

Front 23

oxygen-dept microbial killing

Back 23

myleoperoxidase halide:
If you have both leukocyte enzyme myeloperoxidase and halide ion like chloride, H202 will oxidize microbial proteins and distrupt the cell walls.

Front 24

oxygen independent microbial killing

Back 24

much less effective
mediated by:
lysozyme, MBP of eosinophils

Front 25

Endogenous mediators: vasoactive amines

Back 25

1) histamine--> causes increased capillary permeability

--from basophils, mast cells and platelets

Front 26

Endogenous mediators: arachidonic acid metabolites

Back 26

phospholipase A2 is what stimulates release of arachidonic acid from membrane phospholipids.

1) COX pathway yields
-- platelet TxA2--
vasoconstrictor and platelet aggregant

-- endothelial PGI2--
inhibits platelet aggregation

2) lipoxygenase pathway
yields HPETE
gives rise to leukotrienes (LTB4-chemotactic for neutrophils)

Front 27

Endogenous mediators: cytokines

Back 27

effector melecules that can influence other cells
mediate
immune response (INF-gamma)
inflammation (IL-1 and TNF)

Produce acute phase responses:
--systemic fever
--hepatic synthesis of:
CRP, amyloid, complement, fibrinogen, PT, ferritin, ceruloplasmin
--synthesis of adhesion molecules
--neutrophil degranulation

Front 28

Endogenous mediators: kinin system

Back 28

activated by Hageman factor (XIIa), which LINKS the kinin, coag, plasminogen, and complement systems!!

XIIa also activates kallikrein, which converts HMWK to bradykinin which controls vascular permeability

Front 29

Endogenous mediators: complement system

Back 29

C3a & C5a=anaphalotoxins--mediate degranulation of basophils and mast cells to release histamine

C3b=opsonin

C5b-9=Membrane attack complex (MAC)(lytic for bacteria)

Front 30

Endogenous mediators: Nitric oxide

Back 30

--produced by endothelial cells

--stimulaties relaxation of smooth muscle which helps control vascular tone

--inhibits platelet aggregation, contributing to thromboresistance

Front 31

Outcome of acute inflammation
(other than resolution)

Back 31

1) ABSCESS=
cavity filled with PUS(neutrophils, monocytes and liquefied cell debris)

--results from tissue destruction by lysosomal products and other degradative enzymes

--usually caused by bacterial infections like staph

2) ULCER=
3) FISTULA=
4) SCAR
5) conversion to chronic inflammation:
--PMNs replaced by macs, lymphocytes etc
--new vessels and fibroblasts

Front 32

Hereditary defects that impair acute inflammatory response

Back 32

1) complement deficiency

2)chronic granulomatous DZ of childhood
=deficient NADPH oxidase

=phagocytic cells ingest but can't kill catalase + organisms (like staph)
H2O2 is destroyed and therefore can't use as a substrate for myeloperoxidase system

(note: in catalase neg, enough H202 is made by bacteria, so myeloperox can use this as its substrate

3)myeloperoxisdase deficiency

4) chediak Higashi syndrome (WBCs have abnormal MT formation, so impaired chemotaxis and migration)

5) LAD types 1 & 2

Front 33

Chronic non-specific inflammation

Back 33

1) interaction between macs and lymphocytes

2)fibroblast proliferation + new vessels

3)scarring

Front 34

Granulomatous inflammation

Back 34

1)granulomas=collection of macs called epitheliod cells

2) T-cell lymphocytes activate macs, causing release of cytokines (INF-gamma)

3)have multinucleated giant cells derived from macs

4) caused by:
--TB, leprae, histoplasma
--foreign bodies
--sarcoidosis (unknown cause)
3) Often see with CASEOUS NECROSIS

Front 35

Cell repair: Cell proliferation

Back 35

1) PDGF
--promotes migration of fibroblasts and SM cells
--chemotactic for monocytes

2) EGF (epidermal GF)
--promotes growth of endothelial cells and fibroblasts

3) FGF's (fibroblast GF)
--promote ECM and fibronectin synthesis by fibroblasts, endothelial cells , monocytes.
--fibronectin promotes angiogenesis, and links cell surface integrins and ECM

4) TGF's (transforming GFs)
TGF-a is like EGF
TGF-b is growth inhibitor

5) mac-derived GF's= IL-1 & TNF
--promote prolif of fibroblasts, SM cells, and endothelial cells

Front 36

Wound healing by primary Intention

Back 36

Day 1) FIBRIN CLOT forms and neutrophils infiltrate wound margins

Day 2) MACROPHAGES emigrate into wound

Day 3)Formation of GRANULATION TISSUE=
--highly vascular, newly formed connective tissue made of capillaries + fibroblasts
--fills defects made by liquefaction

2 weeks=collagen compresses BV's in fibrous tissue, so dec blood flow

1 month=collegenase remodeling of wound
(ie, scar tissue formation)

Front 37

what factors can delay/impede repair?

Back 37

1)retention of debris

2) impaired circulation

3) persistent infection

4) metabolic dz like diabetes

5) glucocorticoids (interferes with collagen formation and dec tensile strength)

6)dietary deficiency of ascorbic acid or protein (needed for collagen formation)

Front 38

hemorrhage terminology

Back 38

1) hematoma--localized to tissue or organ

2) hemarthrosis--into synovial space

3) petechiae or purpura=
small hem. in skin, mucus membranes or serosal surfaces

4)ecchymosis
diffuse hemorrhage in skin or sub-q

Front 39

chronic passive congestion

Back 39

1)LUNG
-caused by LH failure or MV stenosis

-distension of alveolar capillaries can lead to rupture and passage of RBCs into alveoli

-phagocytosis of RBCs can result in intra-alveolar hemosiderin-laden mac's called heart-failure cells

2) LIVER
most often by RH failure
Nutmeg liver=
from dilated congested central veins and fatty liver cells

Front 40

Infarction

Back 40

Necrosis from ischemia caused by obstruction of blood supply

1) ANEMIC INFARCTS
-white or pale, caused by arterial occlusions in heart, spleen and kidney

2) HEMORRHAGIC INFACTS
-red infarcts (RBVs ooze into necrotic area)

-see in LUNGS and GI TRACT

-can also be caused by venous occlusion (like incarcerated hernias, post-op adhesions)

Front 41

Define Thrombosis and thrombogenesis

Back 41

thrombosis=
intravascular coag of blood causing significant interruption of flow

thrombogenesis=
results from interaction of platelets, damaged endothelial cells and coag cascade

Front 42

Functions of platelets

Back 42

1) maintain physical integrity of vascular endothelium

2) endothelial repair through contribution of PDGF

3) from platelet plugs

4) promote coag cascade through platelet phospholipid complex

Front 43

reactions involving platelets

Back 43

1) Adhesion -
-vessel injury exposes subendothelial collagen
-glycoprot rec on platelets interacts with subendothelial collagen via: vWF

2) Release Reaction
platelets release ADP, histamine, 5-HT, PDFG

3) activation of coag cascade
conformational change in platelet membrane makes phospholipid complex available, leads to thrombin formation

4) Arachidonic acid metab
proceeds thru COX path to prod TxA2 (a vasoconstrictor and platelet aggregant.)

5)Platelet aggregation
recruit more platelets to produce inital PLUG
--this is promoted by ADP, thrombin, TxA2, collagen, epi, and PAF

6) stabilization of plpug
fibrinogen bridges bind aggregated platelets together, and this mass is stabilized by fibrin

7) limit of plug formation
PGI2 antagonizes TxA2 and limits further aggregation
Fibrin also inhibits aggregation

Front 44

endothelial cells--function in coag

Back 44

1)produce heparin like molecules that activate antithrombin III (this neutralizes thrombin and other coag factors

2) secrete TPA
3) degrade ADP
4) take up, inactivate a& clear thrombin

5)synthesize thrombomodulin--binds thrombin and converts it to APC
NOTE: APC cleaves factors Va and VIIIa, inhibiting coag!

6)synthesize protein S, cofactor for APC
7) releases PGI2
8) releases NO (acts like PGI2)

Front 45

Coagulation: Extrinsic pathway

Back 45

initiated by tissue factor

TF activates factor VII

VIIa activates factor X

Xa (with help of Va as cofactor) converts PT (II) to thrombin (IIa)

***EVALUATE EXTRINSIC PATHWAY BY PT
Thrombin converts fibrinogen-> fibrin

Front 46

Coagulation: Instrinsic pathway

Back 46

involves activation of all clotting factors except VII and XIII

***EVALUATE INTRINSIC BY PTT (partial thromboplastin time)

Front 47

Fibrinolysis/ thrombus dissolution

Back 47

-modulates coagulation

-restores blood flow in vessels blocked by thrombus

PLASMIN=most impt fibrinolytic protease
(splits fibrin)

Front 48

Patterns of inflammation

Back 48

1) Suppurative (purulent)
-local prolif of pus-forming organisms (abscess formation)

2) cellulitis
prolif of bacteria thru subcut tissue

3) Pseudomembranous
bacterial toxin-induced damage of mucosal lining

4) Fibrinous
inc vessel permeability with dep of fibrin-rich exudate along serosal surfaces

5) Ulceration
defect in epithelial lining of skin

6) Fistula

Front 49

Lab findings associated with inflammation:
LEUKOCYTES

Back 49

1)Acute inflammation:
-Absolute Neutrophilic Leukocytosis= rapid release of PMNs from bone marrow mediated by IL-1/TNF

-lots of asurophilic granules

-Left shift: >10% band PMNs or other precursors

2) Chronic inflammation
-absolute monocytosis

Front 50

Lab findings associated with inflammation:
ESR

Back 50

ESR=rate of settling of RBC's in a vertical tube in mm/hr

ESR is elevated in in acute or chronic inflammation

Increase ESR:
1)Plasma factor (inc fibrinogen which dec neg charge in RBCs)

2)RBC's (anemia)

Front 51

Types of Edema
-transudate vs exudate

Back 51

TRANSUDATE= protein-poor & cell-poor
--due to an INC in HYDROSTATIC pressure or DEC in ONCOTIC pressure

--produces pitting edema

EXUDATE=protein rich +cell rich fluid
--due to acute inflammation with inc vascular permeability

--have tissue swelling but no pitting edema

Front 52

embolism:
pulmonary thromboembolism &
arterial embolism

Back 52

embolism=
a detached mass (clot, fat, gas) carried thru blood to a distant site

1) Pulmonary thromboembolism
--most from femoral veins (or pelvic)
--only a few cause pulm infarction

2)Arterial embolism
--most from Left heart (mural thrombus, atrial myxoma etc)

--A-fib predisposes

--COMMON SITES
-lower extremities
-brain via MCA (hemorrhagic infarcts)
-small bowel via SMA (hemorrhagic)
-spleen/kidneys-(pale infarcts)

Front 53

Fat embolism

Back 53

FAT EMBOLISM:
occurs after traumatic fracture of long bones (femur) or pelvis

-fat from bone marrow and adipose lodge in microvasculature
-fatty acids damage vessel endothelium, resulting in platelet thrombi

CLINICAL:
-see 24-72 hours post trauma

-CNS damage: ischemia, hemorrhage

-respiratory failure: hypoxemia

-thrombocytopenia

Front 54

amniotic fluid embolism

Back 54

tear in placental membranes--
infusion of amniotic fluid into maternal circulation and pulmonary vessels

CLINICAL:
-sudden onset of dyspnea, cyanosis, hypotensive shock
-DIC
-maternal death in 80% of cases

Front 55

decompression sickness

Back 55

Inc atmos. pressure causes:
Nitrogen gas to move from alveoli through blood and dissolve in tissues

rapid ascent forces nitrogen gas bubbleds to develop in tissue and lumen of BV's

CLINICAL:
-muscle, joint, bone pain (the "bends")
-hemiparesis
-pneumothorax
-pulmonary embolism

CHRONIC CHANGE=
aseptic necrosis in bones from bone infarctions

Front 56

septic shock

Back 56

mostly assoc with gram-neg infections (often e-coli)

1) endotoxins directly damage endothelial cells, causing release of NO & prostaglandin(vasodilators)

2) endotoxins activate alternative complement pathway, releaseing anaphalotoxins (C3a & C5a) ...more vasodilation of periph. resistance arterioles.

3) IL-1 & TNF released from macs, activate PMN-adhesion molecules

CLINICAL:
1)Increased Cardiac output initially, but tissue unable to remove O2 because of increased flow.

2)Dec LVEDV b/c of PMN emigration from pulm capillaries into alveoli
3)
-warm skin from vasodilation
-increased CO,
-ARDS b/c PMN emigration into alveoli
-DIC from activation of coag system

Front 57

Complications associated with shock

Back 57

1) Ishcemic ATN
mostly PCT in cortex & tubular cells undergo coag necrosis leading to renal failure
**ATN can be reversible!!!

2) pulmonary edema

3) depeletion of lipid in adrenal cortex

4) hemorrhage in colon

5) centrilobular necrosis of liver

6) metabolic acidosis--
due to tissue hypoxia

Front 58

-Glanzmann’s thrombasthenia

Back 58

platelets won't stick together becuase of a mutation in Gp2b3a (needed for platelets to bind fibrinogen and adhere to each other)

Front 59

Asbestosis

Back 59

Asbestosis-very fibrotic
1.Asbestosis: parenchymal fibrosis most severe fibrosis

2.Bronchogenic carcinoma, synergistic effect with cigarette use

3.Pleural effusions

4.Induces pleural fibrous plaques-restrictive lung disease

5.Diffuse pleural fibrosis

6.Mesotheliomas – rare neoplasm arising from mesothelial cells lining the pleura, cigarette smoking not a risk factor. (also house hold members who are exposed to individuals clothing with asbestos at risk)

7.Extrapulmonary neoplasms (Colon, larynx)

8.Serpentine: chrysotiles-most common form-not as harmful

9.Amphiboles: straight, brittle

10.Covered by iron

11.Lung cancer
--Bronchogenic CA
--Mesothelioma

Front 60

Silicosis

Back 60

1. Silicone dioxide (ceramic industry)
2. Sandblasters
3. Slowly progressive
4. Nodular fibrosing pneumonitis-appear identical to very old granuloma (unless stain for silica)
5. Increased risk of TB

Front 61

Coal Workers Pneumoconiosis

Back 61

1. Anthracosis-carbon pigment in Mo
2. Simple coal workers’ pneumoconiosis-moderate deposition of C in lung (majority) minor to no symptoms
3. Progressive massive fibrosis-10%

Front 62

Pneumoconiosis: occupational lung injury

Back 62

Particle Size
1.>5 Trapped in nasal mucosa
2.3-5 um lodge in terminal bronchi/alveolill
3.1-2 um stay suspended in air ;cough out
4.Miner dusts
-Coal dust
-Silica
-Asbestos
-Beryllium
5.Organic particles
6.Chemical fumes
7.Macrophage Phagocytosis
8.Macrophage activation
-Oxygen radicals, and proteases
-LTB4, IL-8, TNF, IL-6
-IL-1, PDGF, IGF-1, TGF-â: profibrotic
9.Chronic inflammation

Front 63

Indoor Pollution

Back 63

1. Carbon monoxide
2. Nitrogen Dioxide
3. Wood Smoke
4. Formaldehyde
5. Radon: second leading cause of lung cancer- in well insulated basements
6. Asbestos fibers
7. Manufactured mineral fibers
8. Bioaerosols

Front 64

Tobacco Smoke

Back 64

1.50% of all smokers will die of tobacco related disease
2.Lung disease
3.Atherosclerosis
4.Cancer-carcinogenic properties of cigarettes
5.Chronic bronchitis emphysema
6.MI
7.Systemic atherosclerosis
8.Bladder, pancreas, esophagus, larynx, and oral cavity cancers
9.Peptic ulcer

Front 65

smoking continued...
pathophys
second hand smoke

Back 65

NOTE: On Xry should see bronchi lines ¨ö way through chest. Instead appears as dead space (hyperinflated due to damage) ¡æ indicative of emphysema

NOTE: Inflammatory response activated by smoking. Neutrophils activated and release protease and ROS. ¥Á-1 antitrypsin moderates neutrophil activation preventing extensive damage

Second-hand Smoke
1.Responsible for
-3,000 lung cancer deaths/yr
-30,000 to 60,000 cardiac deaths/yr

2.Effects on the fetus
-Intrauterine growth retardation (IUGR)
-Spontaneous abortion due to vasospasms

Front 66

Berylliosis

Back 66

1.Nuclear, aerospace industry
2.Acute pneumonitis
3.Pulmonary and Systemic granulomas
-Lymphocyes (no exudate)
-Macrophages –giant cells

Front 67

Chemical Injury

Back 67

1.Dose

2.Requirement for metabolic conversion

3.Sites of absorption, accumulation, excretion

4.Individual variation

5.Capacity of agent to induce immunologic response

Front 68

Estrogens

Back 68

1.Endometrial carcinoma (unopposed estrogen)

2.Breast Cancer

3.Thromboembolism: factor V mutants (2-15% of population)

4.Cardiovascular disease-beneficial

5.Ovarian cancer-protective

6.Estrogens increase the risk of:
--Endometrial cancer
--Breast cancer
--Thromboembolism

7.Recent studies have suggested that estrogens fail to protect women from cardiovascular disease

Front 69

Oral Contraceptives

Back 69

1.Breast cancer: slight or no risk in absence of BRCA mutations

2.Endometrial cancer: no increase risk

3.Ovarian cancer: protective, have actually been prescribed to individuals with BRCA1 mutations

4.Thromboembolism:risk, increased synthesis of coagulation factors, decreased protein C, particularly in older females who smoke

5.Hypertension

6.Hepatic adenoma: increased risk

7.Gallbladder disease: slightly increased risk

8.Does not increase risk, may decrease

Front 70

Analgesics

Back 70

1.Acetaminophen: hepatic necrosis

2.Aspirin (Acetylsalicylic acid)
--Respiratory alkalosis --> metabolic acidosis
-10-30g in adults: 2-4g in children
-Chronic toxicity 3g/d
**Tinnitus
**Erosive gastritis

Front 71

Differences between benign and malignant tumors?

Back 71

1) anaplasia= poorly differentiated

2)pleomorphism

3)hyperchromatism=darkly staining nuclei

4)inc. nuc-cytoplasmic ratio

5) prominent nucleoli